Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X7 receptor

The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X7 receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vdss. Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability. Further attempts to improve the low Vdss of 39 via introduction of amines led to analogs 40 and 41 which maintained the favorable pharmacology profile of 39 and improved Vdss after iv dosing. But these analogs suffered from poor oral absorption, probably driven by poor permeability.